The patent application EP 0 619 370 discloses the use of KGF for wound healing purposes. PDGF may also be used for wound healing purposes as evidenced by its ability to stimulate mesenchymal derived cells, as disclosed in U.S. Pat. No. 5,187,263.
Insulin like growth factors, IGF and IGF-2, have been described and studied in the art. IGF is described in Rinderknecht, J. Biol. Chem. 253:2769 (1978), and has been found to act as a mitogen on a number of different cell types as described in EP 0 128 733. Like insulin, the IGFs stimulate phosphorylation on specific tyrosine residues within the cytoplasmic domain of the receptors to which the IGF binds, as described in WO 93/98826. IGF-II is described in Rinderknecht, FEBS Letters, (1978) 89:283.
Insulin-like growth factors are also known under the class name somatomedins, and have been identified in various animal species as polypeptides that act to stimulate growth of cells in a variety of tissues and cell types, particularly during development. Growth promoting effects of somatomedins include enhancement of cell multiplication and stimulation of cartilage proliferation, stimulation of transport of amino acids, stimulation of synthesis of RNA, DNA and protein, and stimulation of incorporation of sulfate into proteoglycan and of proline into collagen. Much mammalian postnatal growth is due to stimulation of cartilage growth by somatomedins and growth in utero may also be somatomedin-dependent.
Uses of IGF as a known stimulatory and growth promoting agent includes use for bone repair and replacement therapy, as described in EP 303 855; as a means to counteract certain harmful side effects of carcinostatic drugs, as described in JP 63-196524; and as a way to increase lactation and meat production in cattle and other farm animals, as described in U.S. Pat. No. 4,783,524.
IGF-I has also been found useful in the treatment of osteoporosis in mammals exhibiting decreased cortical bone mineral density and those exposed to drugs or environmental conditions that result in bone density reduction and potentially to an osteoporosis condition, as described in EP 560 723 and EP 436 469.
IGF-I has been administered with sodium pentosan polysulfate (PPS) to severely osteoarthritic canines with the effect of reducing the severity of the disease by lowering the levels of active neutral metalloproteinase in the cartilage.
In the model of mildly osteoarthritic canines, therapeutic intervention with IGF-I and PPS together appeared to successfully maintain cartilage structure and biochemistry, while IGF alone was ineffective, as described in Rogachefsky, Osteoarthritis and Cartilage, (1993) 1:105-114.
IGF binding proteins have been studied extensively, and presently six IGFBPs are known (IGFBP 1-6). IGFBPs form complexes with IGF-I and IGF-II in plasma and are believed to function typically as binding proteins for protein hormones, that is regulating the availability, the activity, and extending the half-life of the protein hormone ligand that they transport. While IGFBP-3, a 150 kDa complex, is the most abundant IGFBP in plasma and is believed to function as a carrier and reservoir of IGF-I in plasma, IGFBP-1 is a small 25 kDa binding protein produced mainly in the liver and fibroblasts, and can distribute between the circulation and the tissues, thus potentially regulating the bioavailability of IGF in both compartments as described in Tsuboi et al, J. of Inv. Derm. 104: 199-203 (1995). IGF has been described as useful for wound healing in combination with IGFBP, as described in Tsuboi et al, J. of Inv. Derm. 104: 199-203 (1995), Kratz et al, Scand J Plast Reconsir Hand Surg. 28:107-112 (1994), and Jyung et al, Surgery 115: 233-239 (1994).
IGF expression has been associated with wound healing as described in Gartner et al, J. Surg. Res. 52: 389-394 (1992), and Steenfos and Jansson, Eur. J. Surg. 158: 327-331 (1992). Additionally, IGF has been described as useful when administered in combination with PDGF for wound healing as described in U.S. Pat. No. 4,861,757.
Therefore, it would be advantageous if an improved composition can be found that would have improved properties over administration of PDGF alone, over administration of KGF alone, over PDGF with IGF, and over IGF alone, and over IGF with IGFBP.